MEA6在肿瘤发生过程中的作用及机制研究

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is estimated to be the third and fourth leading cause of cancer deaths in men and women respectively in China. The expression levels of meningioma-expressed antigen-6 (MEA6) have reported to be elevated in different tumors. We found that MEA6 expression is elevated in HCC tissues coincident with the malignancy of tumors and knockdown of MEA6 by RNAi dramatically suppresses the proliferation of liver cancer cells indicating that MEA6 is an oncogene. However, the underlying mechanism has not been explored. We also discovered that MEA6 is a new partner of the TAK1 and IKK complexes which are critical mediators of the TNF-α signaling pathway. It plays a role in TNF-α signaling by interacting with components of the TAK1 and IKK complexes. Here, we are going to investigate whether MEA6 promotes HCC development through the activation of NF-?B, while suppressing JNK activity in the TNF-α signaling pathway and to pursue the potential underlying mechanisms. Our finding is likely to reveal a potential mechanism underlying the association of MEA6 with HCC development and may lead to the development of diagnostic and preventive strategies for HCC.

肝癌在我国男女性癌症中分列第3，4位，恶性程度高，治疗效果差。据报道MEA6在几种肿瘤中异常高表达。我们发现MEA6在肝癌样本中高表达并与肝癌的恶性程度正相关。降低MEA6表达可抑制肿瘤细胞的生长，而高表达MEA6加快细胞生长，显示MEA6可能为肿瘤基因。另外，我们证实MEA6与JNK信号通路的支架蛋白-POSH，以及与肝癌相关的TNFα信号通路蛋白-TRAFs，TAK1，TAB2和IKKs等相互作用。我们过去的研究表明 POSH可与多种致癌或抑癌基因产物互作以调节JNK和NF-κB信号通路及细胞凋亡，这提示MEA6极可能参与与肝癌形成密切相关的TNFα信号通路中JNK和NF-κB活性的调节。我们将通过临床病例和体内（转基因/基因敲除小鼠）研究阐明MEA6是否参与肝癌形成，并通过生化和细胞生物学手段分析MEA6具体的病理生理功能、调节机制和潜在的致癌机制，本研究将为肝癌诊治提供有利的理论。

肝癌在我国男女性癌症中分列第3，4位，恶性程度高，治疗效果差。据报道MEA6在几种肿瘤中异常高表达。我们发现MEA6在肝癌样本中高表达并与肝癌的恶性程度正相关。降低MEA6表达可抑制肿瘤细胞的生长，而高表达MEA6加快细胞生长，显示MEA6可能为肿瘤基因。另外，我们证实MEA6与JNK信号通路的支架蛋白—POSH，以及与肝癌相关的TNFα信号通路蛋白—TRAFs，TAK1，TAB2和IKKs等相互作用。我们过去的研究表明 POSH可与多种致癌或抑癌基因产物互作以调节JNK和NF-κB信号通路及细胞凋亡，这提示MEA6极可能参与与肝癌形成密切相关的TNFα信号通路中JNK和NF-κB活性的调节。我们通过临床病例和体内（转基因/基因敲除小鼠）研究阐明了MEA6对肝癌细胞的生长是必需的，体内敲除MEA6造成严重的脂肪肝。本研究将为肝癌诊治和脂肪肝的发病机理提供有利的理论。